Mooren’s ulcer is an idiopathic peripheral ulcerative keratitis whose pathogenesis is thought to be due to an autoimmune reaction. The first-line treatment for Mooren’s ulcer is the use of topical steroids, which can be difficult to discontinue. The 76-year-old patient in this case was receiving topical steroids for bilateral Mooren’s ulcer and developed a feathery corneal infiltration and perforation in the left eye. On suspicion of a fungal keratitis complication, we started topical voriconazole treatment and performed lamellar keratoplasty. Topical betamethasone was continued twice a day. The identified causative fungus was Alternaria alternata, which is known to be susceptible to voriconazole. The minimum inhibitory concentration of voriconazole was later proven to be 0.5 μg/mL. After 3 months of treatment, the residual feathery infiltration disappeared and the left vision recovered to 0.7. In this case, topical voriconazole was effective, and the eye was successfully treated with continuing topical steroids. Fungal species identification and antifungal susceptibility test proved helpful for symptom management.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Mooren’s ulcer is an idiopathic peripheral ulcerative keratitis whose pathogenesis is thought to be due to an autoimmune reaction [1]. While topical steroids are the first-line treatment for Mooren’s ulcer, they can be difficult to discontinue. In contrast, long-term use of topical steroids sometimes induces infectious keratitis caused by bacteria, fungi, or other microbes. Among these, fungal keratitis is the most refractory. Thus, when there are complications of Mooren’s ulcer due to fungal keratitis, this can make it difficult to treat patients. In this manuscript, we report a case of Alternaria alternata keratitis complicated by bilateral Mooren’s ulcer, which was successfully treated by lamellar keratoplasty and the administration of topical voriconazole with continuing topical steroids.

Case Report

A 76-year-old man with no past history was diagnosed with bilateral Mooren’s ulcer in 2016. The diagnosis was made after excluding rheumatoid arthritis and granulomatosis with polyangiitis based on blood test results that were negative for rheumatoid factor, anti-cyclic citrullinated peptide, and antineutrophil cytoplasmic antibody. Although he was prescribed topical betamethasone, he irregularly utilized the treatment. In December of 2020, his left corneal ulcer worsened, and his previous doctor started combined therapy with 0.1% betamethasone sodium phosphate eye drops and 0.3% gatifloxacin eye drops, which were administered 5 times a day. Due to the development of a feathery corneal infiltration accompanied by oozing of aqueous humor in the left eye, he was referred to our department. Best-corrected visual acuity at his first visit (day 0) was 1.2 and 0.3, while his intraocular pressure was 11 and 6 mm Hg in the right and left eyes, respectively. Although peripheral ulcerative keratitis ranging from the nasal to superior area was observed in both eyes, that of the right eye appeared to be inactive as the ulcer was re-epithelized and there was no ciliary injection (Fig. 1a). The left eye showed ciliary injection, inflammatory cells in the anterior chamber, and fibrin at the pupil. A feathery corneal infiltration was seen at 9 o’clock in the left peripheral cornea (Fig. 1b). We suspected that the left eye had complications associated with fungal keratitis based on the corneal findings and thus, we carefully performed corneal scraping of the lesion. Although neither bacteria nor fungi were detected by direct microscopy, we decided to start topical 0.5% cefmenoxime (6 times a day), 1% voriconazole (6 times a day), and 0.1% betamethasone (twice a day) on the suspicion of a fungal infection. However, the next day (day +1) hypopyon developed, and flattening of the anterior chamber was observed on the third day after the initial visit. As a result, we performed lamellar keratoplasty at day +5. The surgical procedure included adjacent conjunctival resection, an oval shape removal of the necrotic superficial cornea to about 4/5 depth of corneal stroma, debridement of the feather-like lesion, and the reconstruction of the cornea using a lamellar donor cornea (Fig. 2a). On the day after the surgery (day +6), the feathery infiltration remained in the deep corneal stroma. All three of the previously used eye drops were continued after the surgery. At day +14, a black fungal colony grew on a potato-dextrose agar plate, which was identified as an Alternaria species by findings of the DNA sequencing of the internal transcribed spacer (ITS) region of ribosomal DNA (Fig. 3a, b). An antifungal susceptibility test was performed based on the Clinical and Laboratory Standards Institute (CLSI) M38-A2 standard. The minimum inhibitory concentration of voriconazole was 0.5 μg/mL (Table 1). Based on these findings, it was decided to continue the topical voriconazole and betamethasone. As a result, there was gradual improvement of the inflammation of the left eye, with the residual feathery infiltration subsequently disappearing. At 3 months after the initial visit, his left best-corrected visual acuity finally recovered to 0.7 (Fig. 2b). The isolated fungal strain was finally identified as Alternaria alternata through the use of additional DNA sequencing of genes encoding allergenic protein Alt a 1, actin, and calmodulin [2, 3]. The sequences of ITS1 region, Alt a 1, actin, and calmodulin genes were deposited in the DDBJ database (LC794568, LC704879, LC705338, and LC705339, respectively).

Fig. 1.

Slit lamp findings at the first visit show bilateral peripheral ulcerative keratitis that ranged from the nasal to superior areas. While the keratitis in the right eye was inactive (a), the left eye exhibited feathery infiltration at 9 o’clock in the peripheral cornea with ciliary injection, inflammation of the anterior chamber, and fibrin at the pupil (b).

Fig. 2.

Slit lamp findings of the left eye after the lamellar keratoplasty show the oval-shaped lamellar corneal graft in the nasal peripheral cornea. Although the feathery infiltration in the deep stroma remained on the day after the initial surgery (a), it disappeared after 3 months (b).

Fig. 3.

Giant colony of Alternaria alternata isolated in this report. a The colony on a potato-dextrose agar plate appears greenish in color and fuzzy on the surface (28°C, 8 days). b The reverse side was pigmented.

Table 1.

Susceptibility test of antifungal agents

Antifungal agentsMEC/MICa, μg/mLMicafungin0.03Caspofungin0.5Amphotericin B0.5Natamycin1Fluconazole16Itraconazole0.5Voriconazole0.5Miconazole1Discussion

Alternaria species are known as plant pathogenic fungi, which include numerous species that number over 250 species in total [4]. Among these, Alternaria alternata and Alternaria infectoria are the main species reported to cause human infections, such as skin infections after trauma, keratitis, and endophthalmitis [5]. Alternaria species are the third major isolates of fungal keratitis found in Japan, following the Candida and the Fusarium species [6]. Although there have been many cases of Alternaria keratitis reported, there have been few case reports with accurate species identification through the use of DNA sequencing [7, 8]. However, there have been several case reports that have shown the clinical efficacy of topical, oral, or intracameral voriconazole [9–12]. Even so, there is little information regarding the antifungal susceptibility of keratitis-derived Alternaria species.

In our case, fungal keratitis developed in the eye in conjunction with Mooren’s ulcer and which was accompanied by corneal perforation. As a result, we performed lamellar keratoplasty for the corneal perforation, although the feathery corneal infiltration remained in the deep corneal stroma. Another treatment option that could have been potentially used was a penetrating keratoplasty in order to fully excise the lesion. However, we decided to perform lamellar keratoplasty, as this is easier to manage postoperatively, as compared to that for penetrating keratoplasty. Even though treating this proved to be challenging, the causative fungal strain was A. alternata, which has been shown to be highly susceptible for voriconazole in vitro. Thus, in the present case, the DNA sequence-based fungal species identification and antifungal susceptibility test proved to be useful by helping us to determine the final treatment regimen. Moreover, it is also known that topical voriconazole has good penetration into human aqueous humor [13–15]. Therefore, we were able to successfully treat the A. alternata keratitis found in this case by administering topical voriconazole in conjunction with continuing topical steroids. An alternative treatment to the topical steroids that could have also been utilized was the use of a topical cyclosporine as this is a strong immunosuppressant that inhibits calcineurin and has been proven to have antifungal properties [16].

In conclusion, A. alternata keratitis complicated by Mooren’s ulcer was successfully treated through the use of topical voriconazole along with continuing topical steroids. Fungal species identification and an antifungal susceptibility test proved to be helpful for determining a successful treatment for symptom management. The CARE Checklist has been completed by the authors for this case report and is attached as supplementary material.

Statement of Ethics

Ethics approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors have received no funding or grant support for this study.

Author Contributions

Daisuke Todokoro and Tomoko Miyakubo treated the patient and drafted the manuscript. Aya Komori and Takashi Tamura performed the microbiological analysis. Koichi Makimura contributed to the data interpretation. Hideo Akiyama supervised the conduct of this study. All authors reviewed and approved the final version of the manuscript to be published.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to their inclusion of information that could compromise the privacy of the patient.

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